Treatment Orientation and Associated Characteristics of North American Academic Psychiatrists

We present data showing the degree to which a “biological-psychotherapeutic” division persists in American psychiatry, and how psychiatrists' treatment orientation is associated with personal and professional characteristics. Almost two thirds of academic psychiatrists who responded to our survey (N = 435) could be classified as either biological (27%) or psychotherapeutic (37%) in orientation, according to the proportion of their caseload to which they provided psychotherapy (25% vs. ≥75%). There appears to have been an increase over the last 35 years in the proportion of psychiatrists who can be classified as biologically oriented and a decrease in the proportion who can be classified as psychotherapeutically oriented, as well as the emergence of a large class of intermediate or “eclectic” practitioners (36%). Several personal and professional attributes were distributed differentially according to treatment orientation. Psychotherapeutically oriented respondents more frequently reported personal histories of psychiatric disorders than did biologically oriented respondents (64% vs. 39%) as well as greater satisfaction with clinical work (81% vs. 53% “very satisfied”). Differences were also found in age, gender, history of personal psychotherapy, family history of psychiatric disorder, history of marijuana use, degrees of involvement in research, teaching and clinical care of patients, and overall work satisfaction, as well as other characteristics

Sexual orientation and associated characteristics among north american academic psychiatrists

We mailed questionnaires inquiring about a range of personal and professional attributes to 972 North American psychiatrists at five leading medical schools in the United States and Canada. Of these, 49% (435 psychiatrists) responded. Of the respondents, 90.9% reported being exclusively heterosexual, 3.5% predominantly heterosexual, and 5.6% bisexual/homosexual. Analyses were performed to assess the relationship between sexual orientation and other variables. We found that exclusive heterosexuals were more likely than other psychiatrists to be Jewish (p = .002), to have first‐degree relatives with psychiatric illness (p =.015), and to have conducted research after residency training (p = .034). Exclusively heterosexual psychiatrists were less likely to have used recreational drugs (p = .025), or to prescribe psychotropic medications to none of their patients (p = .017). Sexual orientation was not correlated with a variety of other personal and professional characteristics. The findings suggest that gay men and lesbians are represented within psychiatry at rates comparable to their estimated representation in society. Moreover, the data invite several hypotheses—for example, that medical students may be drawn to psychiatry for specific reasons such as feeling marginalized due to being gay or bisexual

Assessment of Hydration Thermodynamics at Protein Interfaces with Grid Cell Theory

Molecular dynamics simulations have been analyzed with the Grid Cell Theory (GCT) method to spatially resolve the binding enthalpies and entropies of water molecules at the interface of 17 structurally diverse proteins. Correlations between computed energetics and structural descriptors have been sought to facilitate the development of simple models of protein hydration. Little correlation was found between GCT-computed binding enthalpies and continuum electrostatics calculations. A simple count of contacts with functional groups in charged amino acids correlates well with enhanced water stabilization, but the stability of water near hydrophobic and polar residues depends markedly on its coordination environment. The positions of X-ray-resolved water molecules correlate with computed high-density hydration sites, but many unresolved waters are significantly stabilized at the protein surfaces. A defining characteristic of ligand-binding pockets compared to nonbinding pockets was a greater solvent-accessible volume, but average water thermodynamic properties were not distinctive from other interfacial regions. Interfacial water molecules are frequently stabilized by enthalpy and destabilized entropy with respect to bulk, but counter-examples occasionally occur. Overall detailed inspection of the local coordinating environment appears necessary to gauge the thermodynamic stability of water in protein structures

Diverse Clonal Fates Emerge Upon Drug Treatment of Homogeneous Cancer Cells

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues

Using the fragment molecular orbital method to investigate agonist–orexin-2 receptor interactions

The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity and is essential for an efficient structure-based drug discovery (SBDD) process. Clearly, to begin SBDD, a structure is needed, and although there has been fantastic progress in solving G-protein-coupled receptor (GPCR) crystal structures, the process remains quite slow and is not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of X-ray crystallography to impact the drug discovery process for GPCR targets in 'real-time' and hence there is still a need for other practical and cost-efficient alternatives. We present here an approach that integrates our previously described hierarchical GPCR modelling protocol (HGMP) and the fragment molecular orbital (FMO) quantum mechanics (QM) method to explore the interactions and selectivity of the human orexin-2 receptor (OX2R) and its recently discovered nonpeptidic agonists. HGMP generates a 3D model of GPCR structures and its complexes with small molecules by applying a set of computational methods. FMO allowsab initioapproaches to be applied to systems that conventional QM methods would find challenging. The key advantage of FMO is that it can reveal information on the individual contribution and chemical nature of each residue and water molecule to the ligand binding that normally would be difficult to detect without QM. We illustrate how the combination of both techniques provides a practical and efficient approach that can be used to analyse the existing structure-function relationships (SAR) and to drive forward SBDD in a real-world example for which there is no crystal structure of the complex available

High-Throughput Structure-Based Drug Design (HT-SBDD) Using Drug Docking, Fragment Molecular Orbital Calculations, and Molecular Dynamic Techniques

Structure-based drug design (SBDD) is rapidly evolving to be a fundamental tool for faster and more cost-effective methods of lead drug discovery. SBDD aims to offer a computational replacement to traditional high-throughput screening (HTS) methods of drug discovery. This "virtual screening" technique utilizes the structural data of a target protein in conjunction with large databases of potential drug candidates and then applies a range of different computational techniques to determine which potential candidates are likely to bind with high affinity and efficacy. It is proposed that high-throughput SBDD (HT-SBDD) will significantly enrich the success rate of HTS methods, which currently fluctuates around ~1%. In this chapter, we focus on the theory and utility of high-throughput drug docking, fragment molecular orbital calculations, and molecular dynamics techniques. We also offer a comparative review of the benefits and limitations of traditional methods against more recent SBDD advances. As HT-SBDD is computationally intensive, we will also cover the important role high-performance computing (HPC) clusters play in the future of computational drug discovery

Using the fragment molecular orbital method to investigate agonist-orexin-2 receptor interactions

Abstract The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity and is essential for an efficient structure-based drug discovery (SBDD) process. Clearly, to begin SBDD, a structure is needed, and although there has been fantastic progress in solving G-protein-coupled receptor (GPCR) crystal structures, the process remains quite slow and is not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of X-ray crystallography to impact the drug discovery process for GPCR targets in 'real-time' and hence there is still a need for other practical and cost-efficient alternatives. We present here an approach that integrates our previously described hierarchical GPCR modelling protocol (HGMP) and the fragment molecular orbital (FMO) quantum mechanics (QM) method to explore the interactions and selectivity of the human orexin-2 receptor (OX 2 R) and its recently discovered nonpeptidic agonists. HGMP generates a 3D model of GPCR structures and its complexes with small molecules by applying a set of computational methods. FMO allows ab initio approaches to be applied to systems that conventional QM methods would find challenging. The key advantage of FMO is that it can reveal information on the individual contribution and chemical nature of each residue and water molecule to the ligand binding that normally would be difficult to detect without QM. We illustrate how the combination of both techniques provides a practical and efficient approach that can be used to analyse the existing structure-function relationships (SAR) and to drive forward SBDD in a real-world example for which there is no crystal structure of the complex available